We propose to study the pathogenetic mechanisms involved in two contrasting models of autoimmune renal disease: (1) glomerulonephritis (AGN) caused by autoantibodies to glomerular basement membrane and mediators of neutrophil chemotaxis and (2) autoimmune renal tubulointerstitial (RTD) disease induced by autoantibodies to tubular basement membrane and chemotactic factors specific for mononuclear cells. Guinea pigs are relatively resistant to the induction of AGN but some do develop severe glomerular lesions involving neutrophils. Both factors, the relative resistance to induction of AGN and a possible method for reproducible induction of AGN will be examined and compared with the findings in RTD. We will obtain data on the nature of the inducing antigen, the immunopathologic activities of autoantibody classes and their interaction with mediators of tissue injury. Secondly, a new model of renal disease in the guinea pig is characterized by tubulointerstitial lesions and the presence of mononuclear cells in the target organ. We have recently delineated some key factors in this pathogenesis: no essential role could be found for C4 because disease in C-deficient guinea pigs was identical to that seen in animals with circulating C4. However, a role for complement was established in complement depletion experiments. We will study the role of complement components and cofactors such as properdin to determine the humoral- celular interactions which take place along renal basement membranes in the development of these contrasting autoimmune lesions. We will ascertain the origin and function of mononuclear cells in RTD using irradiated passive transfer recipients of anti-tubular basement membrane autoantibodies reconstituted with various cells or combinations of cells, such as thymus- derived lymphocytes and macrophages. These experiments will shed light on some unresolved questions in the pathogenesis of human autoimmune renal disease and autoimmune diseases in general. Of particular importance will be the function of the alternate pathway of complement activation in tissue injury since this pathway has become recently implicated in certain human diseases.